Epidemiological studies have clearly established that human papillomas (HPV) infection is a major risk factor for cervical cancer. A number of individuals undergo remission either spontaneously or after clinical intervention, while others, particularly those exhibiting immudeficiency, seem to proceed to develop invasive cancer. It is important to understand the immunological basis for the clinical remission of HPV-associated cervical neoplasia for designing proper intervention strategies. We have determined cell-mediated immunity (CMI) responses specific to synthetic peptides from E6 and E7, the two major oncoproteins of high risk type HPV (HPV-16), in a subset of patients attending the colposcopic clinic. These patients underwent excisional or ablative treatment for cervical intra epithelial neoplasia (CIN) at least six months prior to enrolling in the study. Significant differences were observed in proliferative responses directed against peptides from both the E6 (p=0.002) and E7 (p<0.001) between women without cytological or histological evidence of CIN (disease-free group) and those with a histological diagnosis of recurrence for CIN. Additional pilot studies on in vitro cytokine production mediated by the E6 and E7 peptides, showed a predominant TH1-cytokine profile in women from the disease-free group, while women with disease recurrence exhibited TH2-cytokine responses. On the other hand, none of the women in any of the study groups exhibited circulating antibodies reactive with the E6 and E7 peptides used in the study. Based on our results showing significantly high levels of HPV-peptide-specific TH1 responses in disease-free patients only, we hypothesize that HPV-specific CMI directed against the E6 and E7 oncoproteins is important for protection/recovery from HPV-associated CIN. To test this hypothesis, we propose to conduct a prospective cohort study of women positive for high-risk HPV types and treated for CIN by loop electrosurgical procedure. Our goals are to identify HPV peptides that can potentially serve as markers of protective immunity and for inclusion in immunotherapeutic and/or immunoprophylactic vaccine formulations against HPV-associated CIN. We will assess the pattern of the HPV-specific immunological responses over time, in particular CMI against E6 and E7 peptides corresponding to high-risk HPV types. We will also determine as to whether an association exists between the immune responses and additional HPV-related factors (persistence of infection and HPV type), and other risk factors associated with CIN such as smoking, sexual behavior, intrinsic and extrinsic hormonal factors.